ARTICLE IN BRIEF
A new study presents evidence that a gene regulator known as REST (repressor element 1-silencing transcription factor), long thought to be active only during fetal brain development, reactivates later in life and helps neurons resist oxidative stress as well as the toxic effects of amyloid-beta, neurofibrillary tangles, and other abnormal proteins.
Alzheimer's research has long focused on finding ways to prevent or reduce the accumulation in the brain of amyloid-beta (Abeta), believed to trigger the disease, but a paper published in the March 19 online edition of Nature conjures visions of another strategy — bolstering the ability of neurons to protect themselves from amyloid and other sources of stress.
The paper presents evidence that a gene regulator known as REST (repressor element 1-silencing transcription factor), long thought to be active only during fetal brain development, reactivates later in life and helps neurons resist oxidative stress as well as the toxic effects of Abeta, neurofibrillary tangles, and other abnormal proteins. REST appears to do this by turning off genes that promote pathology and cell death, while turning on genes that somehow bolster stress-response mechanisms within neurons.
Levels of REST, the researchers discovered, correlate tightly with the health of the aging brain.
“REST begins to decline very early in patients with mild cognitive impairment,” said lead author Bruce Yankner, MD, PhD, a professor of genetics and neurology at Harvard Medical School. “Also, animal studies suggest that without REST, neurons become more vulnerable to a variety of toxic insults.”
Conversely, people who have high brain levels of REST appear to be resistant to neurodegeneration even when they carry a large burden of Abeta and other toxic proteins.
A THESIS IN DEVELOPMENT
In the 1990s, Dr. Yankner did seminal work on the toxic effects of amyloid and tau proteins in the brain. Now he focuses on brain aging, and began the research described in the Nature paper by searching for genetic switches that distinguish young brains from old. Tao Lu, PhD, an instructor in genetics at Harvard Medical School and first author of the paper, identified REST as the most strongly activated regulator in the aging brain.
After identifying the genes that REST regulates, the researchers conducted in vitro studies that showed neurons lacking REST were much more vulnerable to oxidative stress produced by redox-active iron, hydrogen peroxide, and other stressors. Also, mice genetically engineered to lack REST lost neurons in the hippocampus and the cortex as they aged. The roundworm Caenorhabditis elegans, often used as a model of aging and stress resistance, contains a functional ortholog of REST known as SPR-4, which protected neurons from oxidative stress and Abeta.
Dr. Yankner and his colleagues then examined brain tissue donated by participants in the Religious Orders Study and the Rush Memory and Ageing Project, longitudinal studies conducted at Rush University Medical Center in Chicago. They found that those with high levels of REST came from people who displayed no symptoms of dementia before death even if their brains contained large amounts of Abeta. However, REST was virtually absent from the nucleus of cortical and hippocampal neurons in people with mild cognitive impairment or Alzheimer's disease.
“The cognitively intact patients had significantly higher REST than the demented patients, despite the fact that their brain pathology was comparable,” Dr. Yankner told Neurology Today.
WHY DO THE REST LEVELS VARY?
But what accounts for the various levels of REST found in the human brain? The researchers determined that to do its job, REST must get into the cell nucleus, but that process was blocked in brain tissue from people with Alzheimer's, frontotemporal dementia, and dementia with Lewy bodies. Instead, REST was destroyed through autophagy.
REST expression in certain neuronal populations also correlated with increased longevity, which suggests that its beneficial effects extend beyond neuroprotection.
“Given that the REST pathway appears to play a role in age-related stress resistance in the brain, it would be very interesting to look at its action in a variety of neurological disorders such as ischemia, stroke, and neurodegenerative disorders such as Parkinson's disease,” Dr. Yankner said. “We're also interested in possible therapeutic applications and compounds that can modulate the REST pathway.”
One possible compound might be lithium, often used to control the fluctuating moods of bipolar disorder. Lithium appears to activate REST, suggesting to Dr. Yankner that the drug might work by maintaining neuronal homeostasis. He pointed to a paper published in 2013 in the EMBO Journal by Italian researchers who found that induced hyperactivity in neurons enhances the expression of REST, which, in turn, down-regulates their firing activity.
“You can imagine that a mechanism like that could contribute to manic-depressive illness by altering the set point,” he said. “I think that is an interesting possibility for the role of REST in neuropsychiatric diseases.”
The paper shows that Alzheimer's disease involves more than plaques and tangles, according to Marek-Marsel Mesulam, MD, FAAN, director of the Cognitive Neurology and Alzheimer's Disease Center at the Northwestern University Feinberg School of Medicine in Chicago.
“This is an incredibly elegant, sophisticated, scholarly paper,” said Dr. Mesulam, the Ruth Dunbar Davee professor in neuroscience at the Feinberg School. “It raises fascinating questions that ought to be pursued. It illustrates that amyloid may not be the linchpin that holds Alzheimer's disease together, and it puts Alzheimer's back on the spectrum of age-related biological changes in the brain. REST basically sits at the crossroads of longevity, aging, and Alzheimer's pathology.”
His only reservation is that REST seems to be too good to be true. “It seems to help you live longer, live well, combat Alzheimer's disease, resist frontotemporal dementia and Lewy body disease,” Dr. Mesulam said. “While it's conceivable that such a thing could exist, the action of REST may be too general to help us understand the biology of aging or of a given disease.”
Veteran Alzheimer's researcher David M. Holtzman, MD, FAAN, agreed that the Nature paper provides strong evidence that the expression of REST in the brain increases in elderly individuals who are cognitively intact, and declines in cases of Alzheimer's and other dementias. “The authors hypothesize that loss of REST expression might explain why some people with Alzheimer's pathology become impaired while others with equal pathology do not,” said Dr. Holtzman, the Andrew B. and Gretchen P. Jones professor and chair of the department of neurology at Washington University School of Medicine in St. Louis. “This is a hypothesis worth testing, but it is a hypothesis. I can think of many future studies that will be helpful in both evaluating the role of REST in Alzheimer's-mediated neurodegeneration, and in determining whether REST might be a path to new treatments.”
However, unlike Dr. Mesulam, Dr. Holtzman does not think REST calls into question the amyloid cascade hypothesis, which regards Abeta as the fundamental instigator of the pathogenesis of Alzheimer's disease. “It is speculation to say at this point that REST is the missing link between Abeta and cognitive decline in Alzheimer's disease,” Dr. Holtzman said. “I think ample evidence shows that Alzheimer's disease is related in many cases to how amyloid-beta is linked to both the spread of tau pathology and tau-mediated neurodegeneration. The potential role of REST looks interesting, but there are no data from an animal model or from humans that REST plays a role in Alzheimer's degeneration. It's really good initial science. They really did a nice job of figuring out how this protein is altered. But the paper doesn't provide enough information to make any conclusions about its role in mediating neurodegeneration in Alzheimer's disease.”
More research is needed to do just that, experts agreed.